Pathological interactions of a-syn, mitochondria, and pesticides in PD models

描述（申请人提供）：帕金森病（PD）是一种常见的晚发性进行性神经退行性疾病，其特征是皮层下神经元群的变性，包括黑质、致密部（SNpc）的多巴胺能神经元，以及由α -突触核蛋白组成的细胞质包涵体的存在。虽然PD的病因尚不清楚，但α -突触核蛋白的遗传和生化异常与PD和其他α -突触核蛋白病的发病机制有直接关系。α -突触核蛋白异常与神经变性之间的因果关系被各种遗传模型所证明，其中α -突触核蛋白异常导致成人发病的神经系统疾病伴神经变性。一些模型表现出人类α -突触核蛋白病的许多特征，包括α -突触核蛋白的异常聚集和皮层下区域的神经变性。我们的研究表明，tg小鼠的α -突触核蛋白病与氧化应激和线粒体异常有关。由于线粒体异常和氧化应激都与PD和其他α -突触核蛋白病的发病机制有关，我们将在Hua-Syn Tg小鼠和细胞模型中研究线粒体功能障碍、氧化应激和α -突触核蛋白病之间的病理关系（目的1和2）。此外，我们的研究表明，α -突触核蛋白转基因小鼠对慢性MPTP治疗诱导的神经变性表现出更高的易感性。因此，α -突触核蛋白、环境因子（如杀虫剂）导致的线粒体功能障碍和神经变性之间可能存在直接的病理联系。我们将使用已知能抑制复合物I活性的农药，通过细胞培养（目标3）和转基因小鼠模型（目标4）来确定这些已知PD危险因素之间的病理相互作用。这些研究将提供与人类α -突触核蛋白病发病机制直接相关的过程的体内实验测试，并可能导致新的治疗方法。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common late onset, progressive neurodegenerative disease characterized by degeneration of subcortical neuronal populations, including dopaminergic neurons of substantia nigra, pars compacta (SNpc), and presence of the cytoplasmic inclusions composed of alpha-synuclein. While the causes of PD are not known, genetic and biochemical abnormalities of alpha-synuclein are directly implicated in the pathogenesis of PD and other alpha-synucleinopathies. Causal link between alpha-synuclein abnormalities and neurodegeneration is shown by various genetic models where alpha-synuclein abnormalities lead to adult- onset neurological disease with neurodegeneration. Some models exhibit many of the features of human alpha-synucleinopathies, including aberrant aggregation of alpha-synuclein and neurodegeneration in subcortical regions. Our studies indicate that alpha-synucleinopathy in tg mice is associated with oxidative stress and mitochondrial abnormalities. Because both mitochondrial abnormalities and oxidative stress are implicated in the pathogenesis of PD and other a-synucleinopathies, we will examine the pathological relationships between mitochondrial dysfunction, oxidative stress and alpha-synucleinopathies in Hua-Syn Tg mice and in cell models (Aims 1 and 2). In addition, our studies show that alpha-synuclein transgenic mice exhibit increased vulnerability to neurodegeneration induced by the chronic MPTP treatment. Thus, there could be a direct pathologic link between alpha-synuclein, mitochondrial dysfunction via environmental agents (such as pesticides), and neurodegeneration. We will use pesticides that are known to inhibit complex I activity to define the pathological interactions between these factors that known risk factors for PD using cell culture (Aim 3) and transgenic mouse models (Aim 4). These studies will provide in vivo experimental tests of processes that are directly relevant to the pathogenesis of human alpha-synucleinopathies and may lead to new therapeutic approaches. PUBLIC HEALTH RELEVANCE: Parkinson's disease and related alpha-synucleinopathies are fatal neurodegenerative diseases affecting ~1,000,000 individuals annually in US. Studies indicate that PD is associated with alpha-synuclein abnormalities, mitochondrial dysfunction, and pesticide exposure. We will determine how intrinsic (alpha- synuclein) and extrinsic (environmental toxins) factors act in concert of pathologically affect mitochondrial function and lead to neurodegeneration. Our finding will lead to better understanding of PD and new targets for therapeutic intervention.